Abstract 5750: Discovery of GSK4418959 (IDE275): A novel, non-covalent, reversible Werner Helicase inhibitor and a new potential therapeutic for the treatment of MSI-H cancers

Recent large-scale genome wide CRISPR screens identified Werner (WRN) Helicase as uniquely essential to cell survival specifically in the microsatellite instability-high (MSI-H) cancer setting. This synthetic lethal relationship elevated WRN as an attractive precision therapeutic target for the treatment of MSI-H cancers, irrespective of tumor type. High-throughput screening identified a hit characterized by low potency inhibition of ATPase function. This poster describes the systematic optimization of this hit resulting in the discovery of clinical candidate GSK4418959, a novel, potent and selective small molecule that binds to WRN in an allosteric pocket and inhibits ATPase and DNA unwinding functions in an ATP-competitive manner. GSK4418959 phenocopies the genetic silencing studies in cells and organoids and accordingly, elicits complete tumor regression in murine xenograft MSI-H models (CDX and PDX) following oral dosing. Importantly, no response is observed in analogous microsatellite stable (MSS) models, exemplifying the precision effect of the WRN inhibition mechanism. GSK4418959 will be investigated as a potential treatment for patients with MSI-H cancer, including those who have been treated with and failed at least one line of checkpoint immunotherapy for their advanced disease. Citation Format: Joshua P. Taygerly, Michael P. DeMartino, Brian T. Jones, Edward J. Brnardic, Joshua E. Cottom, Yang Lee, Diana M. Munoz, Claire Neilan, Sunjay Sethi, Robert A. Reid, Apirat Chaikuad, Lisa M. Shewchuk, Ethan McSpadden, Daniel L. Severance, Kira Campbell, Philip Landis, Jay P. Jain, Richard Zhang, Leng Nickels, Dennis K. Murphy, Hans C. Eberl, Muzaffar Alam, Melissa Fleury, Lara K. Leister, Tessa Lynch-Colameta, James P. Phelan, Michael D. VanHeyst, Amberly B. Sanford, Ann M. Rowley, Hongyi Yu, Anna Rutkowska-Klute, Thilo Werner, Stephan Gade, Damian Hruszkewycz, Tyler Higgins, Xin Linghu, Ian S. Young, An D. Nguyen, Sabrina Bedard, Eldridge N. Nartey, Nanhua Deng, Yang Peng, Jessica L. Schneck, Geeta Sharma, Yanhua Rao, Paul A. Barsanti, Michael A. White, Benjamin Schwartz. Discovery of GSK4418959 (IDE275): A novel, non-covalent, reversible Werner Helicase inhibitor and a new potential therapeutic for the treatment of MSI-H cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5750.